Neurofibromatoses (NF) are genetic disorders of the nervous system. NF comprises three types of disease: Neurofibromatosis 1 (NF-1), Neurofibromatosis 2 (NF-2), and Schwannomatosis. They all have different genetic origins. However, they have a common feature: the development of tumors of the nervous system, particularly of the nerve sheath cell known as a Schwann cell. NF-1 is characterized by the development of neurofibromas associated with peripheral nerves. These benign tumors consist of various cell types, namely a mixture of Schwann cells, perennial fibroblasts and mast cells. The frequency of occurrence is 1 in 3000 persons. The second type, NF2, can be diagnosed by the presence of bilateral vestibular schwannomas, but schwannomas on other cranial and spinal nerves, and meningiomas and ependymomas occur as well. Schwannomas are also benign tumors, and consist of Schwann cells. The frequency of occurrence is approximately 1 in 25,000 persons. The third type of NF is Schwannomatosis, which presents with multiple schwannomas, but not involving the vestibular branch of the auditory nerve. A common and unique feature of this type of NF is severe unrelenting pain. The frequency of occurrence is about 1 in 40,000 persons. As a result, NF patients can suffer learning disabilities, hearing loss, imbalance, blindness, deformation, pain and higher mortality than the unaffected population. Currently, there are no known approved drug therapies for the treatment of NF.
In NF1 and NF2, there is a defect in tumor suppressor proteins, neurofibromin and merlin, respectively. One genetic mutation, INI1, also called SMARCB2 has been associated with Schwannomatosis. Consequently, abnormal Schwann cells present altered proliferation patterns, survival and cell morphology that lead to tumor formation. Normal Schwann cells undergo continuous morphological changes as they develop into myelinating and ensheathing cells. These changes are orchestrated by extracellular signals arising from the axon and basal lamina. The inventors have previously described a signaling pathway that involves the stimulation of ErbB2 and beta-integrin receptors by neuregulin and extracellular matrix molecules, respectively. Receptor stimulation leads to the activation of RhoGTPases, including Rac/Cdc42 and their effector kinase p21-activated kinase, PAK. A terminal kinase in this cascade is LIM kinase (LIMK). There are two LIMK family members, LIMK1 and LIMK2 (collectively “LIMK”). The major LIMK substrate is the actin depolymerizing and severing protein cofilin/ADF. LIMK-dependent phosphorylation of cofilin on serine 3 inactivates and promotes stabilization of the actin cytoskeleton. Moreover, LIMK translocates from focal adhesions, where it modulates cell morphology and motility, to the nucleus where it regulates cell cycle progression and cytokinesis. LIMK can also phosphorylate the cyclic-AMP responsive element-binding protein (CREB) in response to Cdc42/Rac-PAK1 activation suggesting transcriptional regulation activity as well. Recently, it was shown that LIMK signaling further promotes cell survival by p53-mediated transcriptional regulation.